S. Beall

Leiomyoma: genetics, assisted reproduction, pregnancy and therapeutic advances

PurposeUterine leiomyomas are common, benign, reproductive tract tumors affecting a majority of reproductive aged women. They are associated with gynecologic morbidity and detrimentally affect reproductive potential. The etiology of leiomyomas is poorly understood and their diagnosis prior to treatment with Assisted Reproductive Technologies (ART) represents a management dilemma. The purpose of this paper is to review known genetic and molecular contributions to the etiologies of leiomyomas, describe their impact on ART outcomes and reproductive potential, and review alternative therapies and future directions in management.MethodsA critical review of the literature pertaining to genetic component of uterine leiomyomas, their impact on ART and pregnancy and leiomyoma therapeutics was performed.ResultsUterine leiomyomas are characterized by complex molecular mechanisms. Their location and size determines their potential detriment to ART and reproductive function and novel therapeutic modalities are being developed.ConclusionThe high prevalence of uterine leiomyomas and their potential detrimental influence on ART and reproductive function warrants continued well-designed studies to ascertain their etiology, optimal treatment and novel less morbid therapies.

History and challenges surrounding ovarian stimulation in the treatment of infertility

OBJECTIVE To examine the history of superovulation for ovulation induction, its contributions to reproductive medicine, and its impact on multiple births. DESIGN A search of the relevant literature using PubMed and other online tools. RESULT(S) Infertility has been a condition known and studied for thousands of years. However, it was not until this past century that effective treatments were developed. With the advancement of our knowledge of the hypothalamic-pituitary axis, therapies utilizing gonadotropins were developed to stimulate ovulation. Not only could we now treat anovulatory infertility but also induce superovulation for IVF. With these successes came consequences, including increased multiple pregnancies. Several countries recognized the high costs associated with multiple births and implemented regulations on the infertility industry. The rate of triplet and higher-order multiples has declined over the past decade. This is largely attributed to a decreased number of embryos transferred. Nonetheless, the twin rate has remained consistently high. CONCLUSION(S) Superovulation has become a routine medical therapy used for ovulation induction and IVF. With the development of this technology have come effective therapies for infertility and new ethical and medical challenges. Since the advent of gonadotropin therapy we have already developed technologies to improve monitoring and decrease hyperstimulation and high-order multiple pregnancies. In the future we anticipate new tools devised to optimize one embryo for one singleton live birth.

A Unique Egg Cortical Granule Localization Motif Is Required for Ovastacin Sequestration to Prevent Premature ZP2 Cleavage and Ensure Female Fertility in Mice

Monospermic fertilization is mediated by the extracellular zona pellucida composed of ZP1, ZP2 and ZP3. Sperm bind to the N-terminus of ZP2 which is cleaved after fertilization by ovastacin (encoded by Astl) exocytosed from egg cortical granules to prevent sperm binding. AstlNull mice lack the post-fertilization block to sperm binding and the ability to rescue this phenotype with AstlmCherry transgenic mice confirms the role of ovastacin in providing a definitive block to polyspermy. During oogenesis, endogenous ovastacin traffics through the endomembrane system prior to storage in peripherally located cortical granules. Deletion mutants of ovastacinmCherry expressed in growing oocytes define a unique 7 amino acid motif near its N-terminus that is necessary and sufficient for cortical granule localization. Deletion of the 7 amino acids by CRISPR/Cas9 at the endogenous locus (AstlΔ) prevents cortical granule localization of ovastacin. The misdirected enzyme is present within the endomembrane system and ZP2 is prematurely cleaved. Sperm bind poorly to the zona pellucida of AstlΔ/Δ mice with partially cleaved ZP2 and female mice are sub-fertile.